Interferon-γ signaling in human iPSC–derived neurons recapitulates neurodevelopmental disorder phenotypes

Warre-Cornish, Katherine; Perfect, Leo; Nagy, Roland; Duarte, Rodrigo R.R.; Reid, Matthew J.; Raval, Pooja; Mueller, Annett; Evans, Amanda; Couch, Amalie C. M.; Ghevaert, Cédric; McAlonan, Gráinne; Loth, Eva; Murphy, Declan; Powell, Timothy R.; Vernon, Anthony C.; Srivastava, Deepak P.; Price, John

doi:10.1126/sciadv.aay9506

Cited by 76 publications

(126 citation statements)

References 61 publications

(132 reference statements)

Supporting

Mentioning

102

Contrasting

Order By: Relevance

“…This is consistent with the previously observed statistical interaction between maternal infection in gestation and family history of psychiatric disorders in determining the risk of psychosis. 12 , 13 Furthermore, our findings are supported by previous studies showing that immune activation of stem cell-derived neurons from healthy individuals result in downregulation of schizophrenia genes 22 and co-culture of stem cell-derived neurons with immune activated microglia give rise to lasting changes in schizophrenia patient interneurons. 23 …”

Section: Discussionsupporting

confidence: 86%

Maternal immune activation downregulates schizophrenia genes in the foetal mouse brain

Handunnetthi

Hamley

Knight

2021

Brain Communications

View full text Add to dashboard Cite

Susceptibility to schizophrenia is mediated by genetic and environmental risk factors. Maternal immune activation by infections during pregnancy is hypothesized to be a key environmental risk factor. However, little is known about how maternal immune activation contributes to schizophrenia pathogenesis. In this study, we investigated if maternal immune activation influences the expression of genes associated with schizophrenia in foetal mouse brains. We found that two sets of schizophrenia genes were downregulated more than expected by chance in the foetal mouse brain following maternal immune activation, namely those genes associated with schizophrenia through genome-wide association study (fold change = 1.93, false discovery rate = 4 × 10−4) and downregulated genes in adult schizophrenia brains (fold change = 1.51, false discovery rate = 4 × 10−10). We found that these genes mapped to key biological processes, such as neuronal cell adhesion. We also identified cortical excitatory neurons and inhibitory interneurons as the most vulnerable cell types to the deleterious effects of this interaction. Subsequently, we used gene expression information from herpes simplex virus 1 infection of neuronal precursor cells as orthogonal evidence to support our findings and to demonstrate that schizophrenia-associated cell adhesion genes, PCDHA2, PCDHA3 and PCDHA5, were downregulated following herpes simplex virus 1 infection. Collectively, our results provide novel evidence for a link between genetic and environmental risk factors in schizophrenia pathogenesis. These findings carry important implications for early preventative strategies in schizophrenia.

show abstract

Section: Discussionsupporting

confidence: 86%

Maternal immune activation downregulates schizophrenia genes in the foetal mouse brain

Handunnetthi

Hamley

Knight

2021

Brain Communications

View full text Add to dashboard Cite

show abstract

“…We would like to gratefully acknowledge all donors and their families for the tissue provided for this study. We are grateful to Rosy Watkins, Paulina Nowosiad, Rupert Faraway and Roland Nagy for generation and maintenance of Price iPSCs [ 41 , 42 ].…”

Section: Acknowledgementsmentioning

confidence: 99%

Novel epigenetic clock for fetal brain development predicts prenatal age for cellular stem cell models and derived neurons

et al. 2021

Self Cite

View full text Add to dashboard Cite

Induced pluripotent stem cells (iPSCs) and their differentiated neurons (iPSC-neurons) are a widely used cellular model in the research of the central nervous system. However, it is unknown how well they capture age-associated processes, particularly given that pluripotent cells are only present during the earliest stages of mammalian development. Epigenetic clocks utilize coordinated age-associated changes in DNA methylation to make predictions that correlate strongly with chronological age. It has been shown that the induction of pluripotency rejuvenates predicted epigenetic age. As existing clocks are not optimized for the study of brain development, we developed the fetal brain clock (FBC), a bespoke epigenetic clock trained in human prenatal brain samples in order to investigate more precisely the epigenetic age of iPSCs and iPSC-neurons. The FBC was tested in two independent validation cohorts across a total of 194 samples, confirming that the FBC outperforms other established epigenetic clocks in fetal brain cohorts. We applied the FBC to DNA methylation data from iPSCs and embryonic stem cells and their derived neuronal precursor cells and neurons, finding that these cell types are epigenetically characterized as having an early fetal age. Furthermore, while differentiation from iPSCs to neurons significantly increases epigenetic age, iPSC-neurons are still predicted as being fetal. Together our findings reiterate the need to better understand the limitations of existing epigenetic clocks for answering biological research questions and highlight a limitation of iPSC-neurons as a cellular model of age-related diseases.

show abstract

“…Various protocols mimicking viral or bacterial infections during certain stages of development produce persistent cognitive deficits and behavioral changes in adult animals reminiscent of those observed in individuals with ASD 54 . Moreover, transient treatment with interferon-γ during neuronal differentiation of human stem cells was reported to cause induction of ASD-associated genes 55 . While studies of individuals diagnosed with ASD support activation of the immune system in ASD, the pathogenetic role of such immune activity remains unclear 56-59 .…”

Section: Discussionmentioning

confidence: 99%

Infections in childhood and subsequent diagnosis of autism spectrum disorders and intellectual disability: a register-based cohort study

Karlsson

Sjöqvist

Brynge

et al. 2021

Preprint

View full text Add to dashboard Cite

Objective. To explore the associations between childhood infections and subsequent diagnoses of autism spectrum disorder (ASD), intellectual disability (ID) and their co-occurrence. Methods. The association between specialized care for any infection, defined by ICD-codes and later ASD or ID was investigated in a register-based cohort of 556,732 individuals born 1987-2010, resident in Stockholm County, followed from birth to their 18th birthday or December 31, 2016. We considered as potential confounders childrens characteristics, family socioeconomic factors, obstetric complications, and parental histories of both treatment for infection and psychiatric disorders in survival analyses with extended Cox regression models. Residual confounding by shared familial factors was addressed in sibling analyses using within-strata estimation in Cox regression models. Sensitivity analyses with exclusion of congenital causes of ASD/ID and documented risk for infections were also performed. Results. Crude estimates indicated that infections during childhood were associated with later ASD and ID with largest risks observed for diagnoses involving ID. Inclusion of covariates, exclusion of congenital causes of ASD/ID from the population and sibling comparisons highlighted the potential for confounding by both heritable and non-heritable factors, though risks remained in all adjusted models. In adjusted sibling comparisons, excluding congenital causes, infections were associated with later ASD without ID (HR 1.24, 95%CI 1.15-1.33), ASD with ID (1.57, 1.35-1.82) and ID without ASD (2.01, 1.76-2.28). Risks associated with infections varied by age at exposure and by age at diagnosis of ASD/ID. Conclusions. Infections during childhood cannot be excluded in the etiology of ASD, particularly ASD with co-occurring ID.

show abstract

Interferon-γ signaling in human iPSC–derived neurons recapitulates neurodevelopmental disorder phenotypes

Cited by 76 publications

References 61 publications

Maternal immune activation downregulates schizophrenia genes in the foetal mouse brain

Maternal immune activation downregulates schizophrenia genes in the foetal mouse brain

Novel epigenetic clock for fetal brain development predicts prenatal age for cellular stem cell models and derived neurons

Infections in childhood and subsequent diagnosis of autism spectrum disorders and intellectual disability: a register-based cohort study

Contact Info

Product

Resources

About